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EMBO J. 2017 Jun 14;36(12):1669-1687. doi: 10.15252/embj.201695957. Epub 2017 Apr 4.

An aberrant phase transition of stress granules triggered by misfolded protein and prevented by chaperone function.

Author information

1
Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.
2
Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy.
3
Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany alberti@mpi-cbg.de.

Abstract

Stress granules (SG) are membrane-less compartments involved in regulating mRNAs during stress. Aberrant forms of SGs have been implicated in age-related diseases, such as amyotrophic lateral sclerosis (ALS), but the molecular events triggering their formation are still unknown. Here, we find that misfolded proteins, such as ALS-linked variants of SOD1, specifically accumulate and aggregate within SGs in human cells. This decreases the dynamics of SGs, changes SG composition, and triggers an aberrant liquid-to-solid transition of in vitro reconstituted compartments. We show that chaperone recruitment prevents the formation of aberrant SGs and promotes SG disassembly when the stress subsides. Moreover, we identify a backup system for SG clearance, which involves transport of aberrant SGs to the aggresome and their degradation by autophagy. Thus, cells employ a system of SG quality control to prevent accumulation of misfolded proteins and maintain the dynamic state of SGs, which may have relevance for ALS and related diseases.

KEYWORDS:

SOD1; protein aggregation; protein misfolding; proteostasis; stress granules

PMID:
28377462
PMCID:
PMC5470046
DOI:
10.15252/embj.201695957
[Indexed for MEDLINE]
Free PMC Article

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